Composition and process

Abstract

The present specification provides novel analogs of carbacyclin (CBA 2 ), 6a-carba-prostacyclin (6a-carba-PGI 2 ), which have pronounced prostacyclin-like pharmacological activity, e.g., as platelet antiaggregatory agents. Specifically the novel chemical analogs of CBA 2 are those substituted by fluoro (C-5), alkyl (C-9), interphenylene (C-5), and methano (C-6a,9). Further provided are benzindene analogs of CBA 2 and substituted forms thereof, i.e., 9-deoxy-2',9-methano (or 2',9-metheno)-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGF 1 compounds. Also provided are a variety of novel chemical intermediates, e.g., substituted bicyclo[3.3.0]octane intermediates, and chemical process utilizing such intermediates which are useful in the preparation of the novel CBA 2 analogs.

I claim: 
     
       1. The carbacyclin intermediate of formula IV or V: ##STR1## wherein n is one or 2; wherein L 1  is α-R 3  :β-R 4 , α-R 4  :β-R 3 , or a mixture of α-R 3  :β-R 4  and α-R 4  :β-R 3 , and wherein R 3  and R 4  are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R 3  and R 4  is fluoro only when the other is hydrogen or fluoro; wherein M 6  is α-OR 10  :β-R 5  or α-R 5  :β-OR 10 , wherein R 5  is hydrogen or methyl and R 10  is an acid hydrolyzable protective group;   wherein R 27  is (1) --C m  H 2m  --CH 3 , wherein m is an integer from one to 5, inclusive,   (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C 1  -C 3 )alkyl, or (C 1  -C 3 )alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R 27  is phenoxy or substituted phenoxy, only when R 3  and R 4  are hydrogen or methyl, being the same or different,   (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C 1  -C 3 )alkyl, or (C 1  -C 3 )alkoxy, with the proviso that not more than two substituents are other than alkyl,   (4) cis--CH═CH--CH 2  --CH 3 ,   (5) --(CH 2 ) 2  --CH(OR 10 )--CH 3 , wherein R 10  is as defined above, or   (6) --(CH 2 ) 3  --CH═C(CH 3 ) 2  ;     wherein --C(L 1 )--R 27  taken together is (1) (C 4  -C 7 )cycloalkyl optionally substituted by one to 3 (C 1  -C 5 )alkyl;   (2) 2-(2-furyl)ethyl,   (3) 2-(3-thienyl)ethoxy, or   (4) 3-thienyloxymethyl;     wherein R 18  is hydrogen, hydroxy, hydroxymethyl, --OR 10  or --CH 2  OR 10 , wherein R 10  is an acid-hydrolyzable protective group;   wherein R 32  is hydrogen or R 31 , wherein R 31  is a hydroxyl hydrogen protective group; and   wherein Y 1  is trans--CH═CH--, cis--CH═CH--, --CH 2  CH 2  --, or --C.tbd.C--.